Clinical resistance associated with a novel <i>MAP2K1</i> mutation in a patient with Langerhans cell histiocytosis

Azorsa, David O.; Lee, David W.; Wai, Daniel; Bista, Ranjan; Patel, Apurvi; Aleem, Eiman; Henry, M. M.; Arceci, Robert J.

doi:10.1002/pbc.27237

Cited by 15 publications

(12 citation statements)

References 21 publications

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“…During treatment with trametinib, the dosage of desmopressin to control diabetes insipidus was reduced, and the relapsed lesion could be quickly reduced by the reuse of trametinib. However, it has been found that p.Q56_G61delinsR, p.C121S/G128D, and p.98_104delinsQ mutations (of which only the rst was found in this study) may be related to resistance to trametinib (Nelson et al 2015;Azorsa et al 2018), so the e cacy and safety of targeted therapy need to be further studied.…”

Section: Discussionmentioning

confidence: 67%

Clinical study of MAP2K1-mutated Langerhans cell histiocytosis in children

Yang

Wang

et al. 2021

J Cancer Res Clin Oncol

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To analyze the genetic and clinical features of children with MAP2K1-mutated Langerhans cell histiocytosis (LCH). MethodsWe compared the clinical features of 37 children with MAP2K1-mutated LCH with those of the BRAF V600E mutation group (n = 133) and no known mutation group (n = 59) in the same period. ResultsWe found 13 mutations of the MAP2K1 gene, which were mainly concentrated at p.53-62 and p.98-103.The most common mutation site was c.172_186del (12/37). Compared with the BRAF V600E mutation group, the patients with MAP2K1 mutations were mainly characterized by single system multiple bone involvement (P = 0.022), with later disease onset (P = 0.029) as well as less involvement of risk organs, especially liver (P = 0.024). There was no signi cant difference in clinical features compared with the no known mutation group. The 2-year progression-free survival rate of rst-line treatment (ChiCTR1900025783, 07/09/2019) in MAP2K1-mutated patients was 65.6% ± 9.5%. The prognosis of patients with lung involvement was poor [HR (95% CI) = 6.312 (1.769-22.526), P = 0.005]. More progression or relapses could be found in patients with bony thorax involvement (8/17 vs. 2/20, P = 0.023), yet involvements in other sites of bones, such as craniofacial bone involvement (8/26 vs. 2/11, P = 0.688) and limb bone involvement (5/12 vs. 5/25, P = 0.240), were not correlated to disease progression or relapse. ConclusionThe children with MAP2K1-mutated LCH have speci c clinical features requiring clinical strati cation and precise treatment. MAP2K1-mutated patients with lung involvement (especially with bony thorax involvement) had poor prognosis.

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Section: Discussionmentioning

confidence: 67%

Clinical study of MAP2K1-mutated Langerhans cell histiocytosis in children

Yang

Wang

et al. 2021

J Cancer Res Clin Oncol

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“…In addition, several studies have identified a higher proportion of ERK activation than BRAF mutation [5,6,[30][31][32], prompting the exploration for additional activating mutations in the MAPK pathway. Further studies revealed MAP2K1 mutations in 27.5-33% of BRAF WT LCH patients [6,24,[32][33][34]. MAP2K1 encodes mitogenactivated protein kinase kinase 1 (MEK1), which is the downstream of the RAF family in the MAPK pathway.…”

Section: Recurrent Somatic Mutations In Langerhans Cell Histiocytosismentioning

confidence: 99%

Signaling pathways, microenvironment, and targeted treatments in Langerhans cell histiocytosis

Gao

Cao

2022

Cell Commun Signal

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Langerhans cell histiocytosis (LCH) is an inflammatory myeloid malignancy in the “L-group” histiocytosis. Mitogen-activated protein kinase (MAPK) pathway activating mutations are detectable in nearly all LCH lesions. However, the pathogenic roles of MAPK pathway activation in the development of histiocytosis are still elusive. This review will summarize research concerning the landscape and pathogenic roles of MAPK pathway mutations and related treatment opportunities in Langerhans cell histiocytosis.

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“…Deciphering the efficacy of MAPKi newly prescribed in histiocytic neoplasms, data on resistance mechanisms in this rare disease are beginning to emerge. Recently, a novel MAP2K1 mutation was related to resistance in a patient treated with trametinib [95]. Similarly, RASA1 loss was highlighted as a mechanism of resistance to BRAFi treatment which was overcome by adding a MEKi [96].…”

Section: Resistance Mechanismsmentioning

confidence: 99%